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1. to conduct a clinical investigation to determine if inhaled epoprostenol (Veletri®, iEPO) and inhaled nitric oxide (iNO) will have similar impact on outcomes in adult patients undergoing durable LVAD placement, heart transplantation, or lung transplantation 2. to conduct a cost-capture analysis on the expense each drug incurs per patient.
In adult cardiothoracic surgical patients, iNO is used to treat precapillary pulmonary hypertension (PH), right-sided heart failure (RHF), and ventilation-to-perfusion (V:Q) mismatch. Adult patients who undergo durable LVAD implantation (e.g. Heartware®, Heartmate 2®, or Heartmate 3®), cardiac transplantation for HFrEF, or those that have endured lung transplantation as a result of end-stage lung disease, compose the largest subpopulation which receives iPVD therapy at Duke University Hospital. iEPO may display an equivalent efficacy profile to iNO for pulmonary vasodilation and oxygenation and have a similar impact on clinical outcomes.
Subjects undergoing LVAD placement or heart transplantation (N=224) or lung transplantation (N=200) will be prospectively enrolled over a three-year period (one-year for follow-up). Patients will be randomly assigned 1:1 according to stratified randomization blocking either iNO or iEPO. Additional study procedures will involve data collection, blood, and tissue sampling.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Lung transplant with iNO | Active Comparator |
| |
| Lung transplant with iEPO | Active Comparator |
| |
| Heart transplant & LVAD implantation with iNO | Active Comparator |
| |
| Heart transplant & LVAD implantation with iEPO | Active Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| iNO | Drug | Subject will receive inhaled Nitric Oxide in this intervention |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Grade 3 Primary Graft Dysfunction (PGD) for Lung Transplant Subjects | This is defined by the International Society of Heart and Lung Transplantation (ISHLT) as severe hypoxemia with a PaO2-to-FiO2 ratio < 200 or the presence of venovenous extracorporeal membrane oxygenation (VV ECMO) at a time-point within the first 72 hours after lung transplantation. | Up to 72 hours |
| Number of Participants With Moderate or Severe RV Failure for the LVAD Implantation Subjects and Severe RV Failure for Heart Transplantation Subjects | This is defined by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) score of moderate or severe right-heart failure for LVADS, and by the incidence of an RVAD placement or ECMO for RHF for heart transplants. | up to approximately 21 days after LVAD placement, up to approximately 30 days after heart transplantation |
| Measure | Description | Time Frame |
|---|---|---|
| Duration of Postoperative Mechanical Ventilation | Length of time from intubation until patient is extubated | up to approximately 90 days after index surgery |
| Per Patient Inhaled Pulmonary Vasodilator (iPVD) Cost |
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Inclusion Criteria:
Exclusion Criteria:
Combined Organ Transplantation
Age < 18 years old
Pregnancy
Known allergy to prostaglandin (rare)
Refusal of blood products due to personal or religious preference
Subject is enrolled in another study protocol, which does not allow randomization of PVD therapy
Heart transplant or durable LVAD recipients with adult congenital heart disease (CHD)
o Caveat: Does NOT meet exclusion criteria if the scheduled heart transplant or LVAD implantation is due to heart failure from a previous heart transplantation related to CHD, performed more than 90 days previous to the date of trial enrollment
Heart transplant recipients diagnosed with Arrythmogenic Right Ventricular Cardiomyopathy
Heart transplant recipients diagnosed with Acute Cardiac Allograft Rejection after a previous heart transplantation.
Heart transplant or durable LVAD recipients with preoperative RVAD for right heart failure
Patient is scheduled to undergo lung transplantation but has undergone heart transplantation in the previous 90 days
Patient is scheduled to undergo durable LVAD implantation but has undergone heart transplantation in the previous 90 days
Patient is scheduled to undergo heart transplantation but has undergone lung transplantation in the previous 90 days
Patients with preoperative Venovenous ECMO as a bridge to lung transplantation
Heart transplant or durable LVAD recipients with preoperative RVAD for right heart failure
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| Name | Affiliation | Role |
|---|---|---|
| Kamrouz Ghadimi, MD | Duke Health | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Duke Health | Durham | North Carolina | 27710 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37401479 | Derived | Ghadimi K, Cappiello JL, Wright MC, Levy JH, Bryner BS, DeVore AD, Schroder JN, Patel CB, Rajagopal S, Shah SH, Milano CA; INSPIRE-FLO Investigators. Inhaled Epoprostenol Compared With Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery. Circulation. 2023 Oct 24;148(17):1316-1329. doi: 10.1161/CIRCULATIONAHA.122.062464. Epub 2023 Jul 4. | |
| 34787647 |
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519 participants were randomized, but 87 of those were unable to undergo surgery on protocol. 432 participants started the study (i.e., underwent surgery on protocol).
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| ID | Title | Description |
|---|---|---|
| FG000 | Lung Transplant With iNO | iNO: Subject will receive inhaled Nitric Oxide in this intervention |
| FG001 | Lung Transplant With iEPO | iEPO: Subject will receive inhaled Epoprostrenol in this intervention |
| FG002 | Heart Transplant & LVAD Implantation With iNO | iNO: Subject will receive inhaled Nitric Oxide in this intervention |
| FG003 | Heart Transplant & LVAD Implantation With iEPO | iEPO: Subject will receive inhaled Epoprostrenol in this intervention |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Patients who were consented and randomized, but excluded or withdrawn prior to surgery and treatment are not included in this cohort description. No participant data was retained after patient exclusion or withdrawal prior to surgery and treatment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Lung Transplant With iNO | iNO: Subject will receive inhaled Nitric Oxide in this intervention |
| BG001 | Lung Transplant With iEPO | iEPO: Subject will receive inhaled Epoprostrenol in this intervention |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Grade 3 Primary Graft Dysfunction (PGD) for Lung Transplant Subjects | This is defined by the International Society of Heart and Lung Transplantation (ISHLT) as severe hypoxemia with a PaO2-to-FiO2 ratio < 200 or the presence of venovenous extracorporeal membrane oxygenation (VV ECMO) at a time-point within the first 72 hours after lung transplantation. | Only applicable to lung transplant patients on protocol. | Posted | Count of Participants | Participants | Up to 72 hours |
|
Collected from surgery to one year.
Patients who were consented and randomized, but excluded or withdrawn prior to surgery and treatment are not included in this cohort description. No participant data was retained after patient exclusion or withdrawal prior to surgery and treatment. Due to the nature of the study design, comparative trial evaluating two standard of care medications, the only SAE reported is mortality at specified intervals.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Lung Transplant With iNO | iNO: Subject will receive inhaled Nitric Oxide in this intervention |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| All Cause Mortality | General disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Venous Thromboemolic DVT | Blood and lymphatic system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Kamrouz Ghadimi, M.D., M.H.Sc. | Duke University | 919-681-6532 | kamrouz.ghadimi@duke.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 26, 2018 | Sep 27, 2021 | Prot_SAP_000.pdf |
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| iEPO | Drug | Subject will receive inhaled Epoprostrenol in this intervention |
|
|
Data reflects a per patient cost in dollars that has been scaled to a unit of measure relative to the cost per hour of drug and multiplied by the duration of iPVD administration. In our study, iNO cost 7 times that of iEPO per hour, hence for each patient this outcome value is the duration of iPVD administration multiplied by 7 if a patient is randomized to iNO or multiplied by 1 if randomized to iEPO.
| up to approximately 30 days after index surgery |
| Length of ICU Stay | Length of time from ICU admission from surgery until ICU discharge | up to approximately 90 days after index surgery |
| Length of Hospital Stay | Length of time from surgery to hospital discharge | up to approximately 1 year after index surgery |
| Number of Participants With Acute Kidney Injury | defined by Modified KDIGO-AKI definition:
| up to approximately 14 days |
| Number of Participants With In-hospital Mortality | Death that occurs during the hospital stay | up to approximately 1 year after index surgery |
| Number of Participants With Post-operative Mortality Within 30 Days | From the day of surgery to 30 days postoperatively. | up to approximately 30 days after index surgery |
| Number of Participants With Post-operative Mortality Within 90 Days | From the day of surgery to 90 days after index surgery | up to approximately 90 days after index surgery |
| Ghadimi K, Cappiello J, Cooter-Wright M, Haney JC, Reynolds JM, Bottiger BA, Klapper JA, Levy JH, Hartwig MG; INSPIRE-FLO Investigators. Inhaled Pulmonary Vasodilator Therapy in Adult Lung Transplant: A Randomized Clinical Trial. JAMA Surg. 2022 Jan 1;157(1):e215856. doi: 10.1001/jamasurg.2021.5856. Epub 2022 Jan 12. |
| BG002 | Heart Transplant & LVAD Implantation With iNO | iNO: Subject will receive inhaled Nitric Oxide in this intervention |
| BG003 | Heart Transplant & LVAD Implantation With iEPO | iEPO: Subject will receive inhaled Epoprostrenol in this intervention |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
iEPO: Subject will receive inhaled Epoprostrenol in this intervention
|
|
|
| Primary | Number of Participants With Moderate or Severe RV Failure for the LVAD Implantation Subjects and Severe RV Failure for Heart Transplantation Subjects | This is defined by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) score of moderate or severe right-heart failure for LVADS, and by the incidence of an RVAD placement or ECMO for RHF for heart transplants. | Only applicable to heart transplant and LVAD implantation cohort that were treated on protocol. | Posted | Count of Participants | Participants | up to approximately 21 days after LVAD placement, up to approximately 30 days after heart transplantation |
|
|
|
|
| Secondary | Duration of Postoperative Mechanical Ventilation | Length of time from intubation until patient is extubated | Among patients extubated, if patients transitioned directly from intubation to tracheostomy the duration of mechanical ventilation was censored at the time of tracheostomy placement | Posted | Median | Inter-Quartile Range | hours | up to approximately 90 days after index surgery |
|
|
|
|
| Secondary | Per Patient Inhaled Pulmonary Vasodilator (iPVD) Cost | Data reflects a per patient cost in dollars that has been scaled to a unit of measure relative to the cost per hour of drug and multiplied by the duration of iPVD administration. In our study, iNO cost 7 times that of iEPO per hour, hence for each patient this outcome value is the duration of iPVD administration multiplied by 7 if a patient is randomized to iNO or multiplied by 1 if randomized to iEPO. | Posted | Mean | Standard Deviation | relative cost units | up to approximately 30 days after index surgery |
|
|
|
| Secondary | Length of ICU Stay | Length of time from ICU admission from surgery until ICU discharge | Posted | Median | Inter-Quartile Range | days | up to approximately 90 days after index surgery |
|
|
|
|
| Secondary | Length of Hospital Stay | Length of time from surgery to hospital discharge | Posted | Median | Inter-Quartile Range | days | up to approximately 1 year after index surgery |
|
|
|
|
| Secondary | Number of Participants With Acute Kidney Injury | defined by Modified KDIGO-AKI definition:
| Posted | Count of Participants | Participants | up to approximately 14 days |
|
|
|
|
| Secondary | Number of Participants With In-hospital Mortality | Death that occurs during the hospital stay | Posted | Count of Participants | Participants | up to approximately 1 year after index surgery |
|
|
|
| Secondary | Number of Participants With Post-operative Mortality Within 30 Days | From the day of surgery to 30 days postoperatively. | Posted | Count of Participants | Participants | up to approximately 30 days after index surgery |
|
|
|
|
| Secondary | Number of Participants With Post-operative Mortality Within 90 Days | From the day of surgery to 90 days after index surgery | Posted | Count of Participants | Participants | up to approximately 90 days after index surgery |
|
|
|
| 9 |
| 98 |
| 9 |
| 98 |
| 42 |
| 98 |
| EG001 | Lung Transplant With iEPO | iEPO: Subject will receive inhaled Epoprostrenol in this intervention | 10 | 103 | 10 | 103 | 41 | 103 |
| EG002 | Heart Transplant & LVAD Implantation With iNO | iNO: Subject will receive inhaled Nitric Oxide in this intervention | 10 | 111 | 10 | 111 | 40 | 111 |
| EG003 | Heart Transplant & LVAD Implantation With iEPO | iEPO: Subject will receive inhaled Epoprostrenol in this intervention | 21 | 120 | 21 | 120 | 48 | 120 |
| Venous Thromboembolic PE | Blood and lymphatic system disorders | Systematic Assessment |
|
| Venous Thromboembolic Other | Blood and lymphatic system disorders | Systematic Assessment |
|
| Arterial Thromboembolic TIA | Blood and lymphatic system disorders | Systematic Assessment |
|
| Arterial Thromboembolic CVA/Stroke | Blood and lymphatic system disorders | Systematic Assessment |
|
| Arterial Thromboembolic Myocardial Infarction | Blood and lymphatic system disorders | Systematic Assessment |
|
| Arterial Thromboembolic Mesenteric Ischemia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Arterial Thromboembolic Other | Blood and lymphatic system disorders | Systematic Assessment |
|
| LVAD Thrombosis | Blood and lymphatic system disorders | Systematic Assessment |
|
| New Onset Atrial Fibrillation | Cardiac disorders | Systematic Assessment |
|
| Upper GI Bleed | Gastrointestinal disorders | Systematic Assessment |
|
| Lower GI Bleed | Gastrointestinal disorders | Systematic Assessment |
|
| Intestinal Perforation | Gastrointestinal disorders | Systematic Assessment |
|
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| Hodges-Lehmann Location Shift |
| 0 |
| 2-Sided |
| 95 |
| -1 |
| 1 |
| Other |
| mean ratio |
| 0.94 |
| 2-Sided |
| 95 |
| 0.57 |
| 1.56 |
| Other |
| mean ratio |
| 0.97 |
| 2-Sided |
| 95 |
| 0.73 |
| 1.28 |
| Other |
| Odds Ratio (OR) |
| 1.2 |
| 2-Sided |
| 95 |
| 0.58 |
| 2.5 |
| Other |
| Odds Ratio (OR) |
| 0.6 |
| 2-Sided |
| 95 |
| 0.17 |
| 2.12 |
| Other |